Detection and reduction of phrenic nerve stimulation

ABSTRACT

The present invention provides implantable medical devices for detecting phrenic nerve stimulation. A pacing module is configured to deliver pacing pulses having a predetermined pulse amplitude and/or width within the refractory period of the left ventricle. The pacing pulses are repeatedly delivered during a number of cardiac cycles, and the pacing pulses are delivered at different delays relative to an onset of the refractory period of the left ventricle in different cardiac cycles. An impedance measurement module is configured to measure impedance signals in time windows synchronized with the delivery of pacing pulses in the refractory period of the left ventricle. A phrenic nerve stimulation, PNS, detection module is configured to gather at least one impedance signal from each time window, create aggregated impedance signals using the impedance signals from the different time windows, and analyze the aggregated impedance signals to detect PNS.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is related to U.S. patent application Ser. No.13/545,794, filed Jul. 10, 2012, titled “Detection and Reduction ofPhrenic Nerve Stimulation”.

FIELD OF THE INVENTION

The present invention relates generally to methods and implantablemedical devices and more particularly to methods and devices fordetecting and reducing undesired phrenic nerve stimulation.

BACKGROUND OF THE INVENTION

Implantable cardiac stimulation devices are well known in the art. Suchdevices may include, for example, implantable cardiac pacemakers anddefibrillators either alone or combined in a common enclosure. Thedevices are generally implanted in a pectoral region of the chestbeneath the skin of a patient within what is known as a subcutaneouspocket. The implantable devices generally function in association withone or more electrode(-s) carrying leads which are implanted within theheart. The electrodes are positioned within the heart for makingelectrical contact with the muscle tissue of respective heart chamber.Conductors within the leads connect the electrodes to the device toenable the device to deliver the desired electrical therapy. Hence,cardiac rhythm management devices are implantable devices that provideelectrical stimulation to selected chambers of the heart in order totreat disorders of cardiac rhythm. Common conditions for whichpacemakers are used are the treatment of bradycardia, where theventricular rate is too low, and heart failure.

A programmable electronic controller of the device causes pacing pulsesto be output in response to lapsed timing intervals and sensedelectrical activity (i.e. intrinsic heart beats not as a result of apacing pulse). Pacemakers sense intrinsic cardiac electrical activity bymeans of electrodes disposed near the chamber to be sensed. Adepolarization wave associated with an intrinsic contraction of theatria or ventricles that is detected by the pacemaker is referred to asan atrial sense or ventricular sense, respectively. In order to causesuch a contraction in the absence of an intrinsic beat, a pacing pulse(either an atrial pace or ventricular pace) with energy above a certainpacing threshold is delivered to the chamber via the same electrode orvia other electrodes than used for sensing the chamber.

Bi-ventricular pacing provides therapy options for a patient sufferingfrom heart failure. However, new challenges have been presented byplacement of the left-ventricular lead via the coronary sinus inbi-ventricular pacing systems. Due to the proximity of the coronaryveins to the phrenic nerve, left ventricular pacing may result inundesirable phrenic nerve stimulation. The left phrenic nerve, whichprovides innervation for the diaphragm, arises from the cervical spineand descends to the diaphragm through the mediastinum where the heart issituated. As it passes the heart, the phrenic nerve courses along thepericardium, superficial to the left atrium and left ventricle. Becauseof its proximity to the electrodes used for pacing, the nerve can bestimulated by a pacing pulse. The resulting involuntary contraction ofthe diaphragm can be annoying to the patient and may also interfere withbreathing.

Accordingly, there exist various methods and devices for detecting andreducing phrenic nerve stimulation of cardiac pacing systems within theart.

In U.S. Pat. No. 7,392,086 to Sathaye methods involving delivery ofpacing pulses, sense of transthoracic impedance signals following thepacing pulses and analysis of deviations in the transthoracic impedancesignals are disclosed. More specifically, a transthoracic impedancesignal is analysed in a time window following a left-ventricular pacepulse, e.g. 500 milliseconds long time windows starting at the deliveryof a left-ventricular pulse, by comparison with a transthoracicimpedance signal resulting from an additional pulse delivered during acardiac refractory period of the left ventricle to find deviationsindicating phrenic nerve stimulation. A threshold test for the availableparticular pacing vectors may be performed to find and select the bestvector in terms of desirable energy levels and reduced phrenic nervestimulation.

In U.S. Patent Application No. 2010/0305638 to McCabe et al, methods forphrenic nerve activation detection and phrenic nerve activationavoidance are disclosed. According to these methods, impedance is usedto identify portions or phases of respiration of interest for detectionof phrenic nerve stimulation. Accelerometer signals or other vibrationsignals are used to detect diaphragmatic response due to phrenic nervestimulation. The detection is performed within a detection windowinitiated based on delivery of a left ventricular pulse during arespiration phase of interest.

In U.S. Patent Applications Nos. 2003/0065365 and 2005/0060002 both toZhu et al., a cardiac rhythm management device in which an accelerometeris used to detect diaphragmatic or other skeletal muscle contractionassociated with output of a pacing pulse are disclosed. Upon detectionof diaphragmatic contraction, the device may adjust pacing pulse energyand/or pacing configuration.

However, there is still a need within the art for improved methods anddevices for detecting phrenic nerve stimulation and for reducing thepresence of phrenic nerve stimulation.

SUMMARY OF THE INVENTION

An object of the present invention is to provide improved methods anddevices for detecting undesired phrenic nerve stimulation.

A further object of the present invention is to provide improved methodsand devices for reducing undesired phrenic nerve stimulation.

Another object of the present invention is to provide improved methodsand devices for increasing the accuracy in the phrenic nerve stimulationdetection.

These and other objects of the present invention are achieved by meansof an implantable medical device and a method having the featuresdefined in the independent claims. Embodiments of the invention arecharacterized by the dependent claims.

According to an aspect of the present invention, there is provided animplantable medical device connectable to a plurality of electrodeselectrically coupled to a heart of a patient in at least one electrodeconfiguration. The device comprises a pacing module configured todeliver pacing pulses to the heart using the at least one electrodeconfiguration and a control module configured to instruct the pacingmodule to deliver pacing pulses having a predetermined pulse amplitudeand/or width within the refractory period of the left ventricle, whereinthe pacing pulses are repeatedly delivered during a number of cardiaccycles and wherein the pacing pulses are delivered at different delaysrelative to an onset of the refractory period of the left ventricle indifferent cardiac cycles. An impedance measurement module is configuredto measure impedance signals in time windows synchronized with thedelivery of pacing pulses in the refractory period of the left ventricleusing at least one electrode configuration. Further, a phrenic nervestimulation, PNS, detection module is configured to gather at least oneimpedance signal from each time window, create aggregated impedancesignals using the impedance signals from the different time windows andanalyze the aggregated impedance signals to detect PNS.

According to another aspect of the present invention, there is provideda method for detecting PNS. The method comprises delivering pacingpulses having a predetermined pulse amplitude and/or width within therefractory period of the left ventricle using at least one electrodeconfiguration, wherein the pacing pulses are repeatedly delivered duringa number of cardiac cycles and wherein the pacing pulses are deliveredat different delays relative to an onset of the refractory period of theleft ventricle in different cardiac cycles and measuring impedancesignals in time windows synchronized with the delivery of pacing pulsesin the refractory period of the left ventricle using at least oneelectrode configuration. Further, at least one impedance signal fromeach time window is gathered, aggregated impedance signals using thegathered impedance signals from the different time windows are createdand the aggregated impedance signals are analyzed to detect PNS.

The present invention is based on the insight that the excursions ordeviations of the impedance signal caused by the phrenic nervestimulation, PNS, move in time in synchronism with the stimulation pulsedelivered to the left ventricle and hence can be used for detection ofPNS with a high degree of accuracy. Stimulation pulses are delivered ina small time window inside the refractory period of the left ventricleto ensure that stimulation of the ventricles are avoided at the sametime as it can be detected whether the delivery of the stimulation pulseresults in a PNS. The time windows are broad enough to capture the PNScaused excursions or deviations, and are synchronized with thestimulation pulse in the left ventricle. The stimulation pulses aredelivered with different timings relative to the onset of the refractoryperiod of the left ventricle and since the time windows are synchronizedwith the stimulation pulses, the time windows will move from beat tobeat relative the refractory period of the left ventricle. The impedancesignals are recorded within the time windows and are collected beat bybeat. The impedance signal measured during a PNS will demonstratesignificant morphological excursions or deviations caused by the PNScompared to non-PNS impedance signals. Hence, if a PNS occur there existPNS footprints in the impedance signals that can be used for the PNSdetection. By creating an aggregated impedance signal based onmeasurements during several time windows, each comprising a pacestimulated PNS, the PNS footprint can be enhanced due to the synchronyof the pace delivery and the PNS excursion or deviation in the impedancesignal. Thus, the PNS content of the impedance signals can be enhancedby synchronized summation of the signals of the time windows and the PNScontent is expected to sum up while uncorrelated signal content withinthe time windows will be reduced.

According to embodiments of the present invention, PNS templates arecreated reflecting an impedance signal without PNS content or reflectingan impedance signal including a PNS event. In the first case, detectionof PNS can be made by comparing a recorded impedance signal (e.g. anaggregated signal based on recordings from several time windows) with asuitable template and PNS is detected if the recorded impedance signaldeviates from the template signal by at least a predetermined limitvalue. In the second case, i.e. a template with verified PNS content,detection of PNS can be made by comparing a recorded impedance signal(e.g. an aggregated signal based on recordings from several timewindows) with the suitable template and PNS is detected if a deviationbetween the recorded impedance signal and the template signal is below apredetermined limit value. The comparison can be made on awindow-by-window basis, i.e. the impedance signal in each window issubtracted from the template signal and the difference signal can thenbe processed to determine whether a deviation is above a limit (in casethe template is free from PNS content) or below a limit (in case thetemplate includes verified PNS content).

According to embodiments of the present invention, it is verified by thepatient and/or by the physician whether a PNS occurred or not during thetemplate creation. For example, if the template creation takes place ata clinic, the physician may place a hand on the chest of the patientduring the template creation procedure to judge whether a PNS hasoccurred or not by sensing if spasms or twitches occur in the diaphragm.The physician may thereafter notify the medical device that a PNS hasoccurred or not using an extracorporeal device such as a programmercapable of communicating with the implanted device. The PNS detectionmodule may hence be configured to receive a verification whether a PNShas occurred or not during the gathering of impedance signals, theverification being received from an extracorporeal unit via acommunication module of the implantable medical device and determinewhether a created impedance signal template is a template with PNScontent or without PNS content depending on the received verification.In an alternative embodiment, the patient may provide the feedback tothe medical device, for example if the template creation procedure isperformed at home, by sensing if spasms or twitches occur in thediaphragm. The implanted device may be notified via an external unitplaced at the home of the patient capable of communicating with theimplanted device. This can be executed with or without supervision of aphysician from a remote clinic.

According to embodiments of the present invention, the deviceautomatically verifies whether a PNS has occurred or not during thetemplate creation procedure. The PNS detection module is configured to,during a template creation procedure, analyze the gathered impedancesignals to determine whether a PNS has occurred or not. This includes,for each time window, calculating the frequency content of the impedancewaveform, determining a frequency content related to respiration, anddetecting that a PNS has occurred if the frequency content related torespiration is above a predetermined frequency content limit anddetermining whether a created impedance signal template is a templatewith PNS content or without PNS content depending on whether a PNS wasdetected or not. If impedance signals are obtained from a number ofdifferent impedance measurement vectors, these can be analyzed in thefrequency plane with regard to the respiration content in relation tothe heart frequency components and/or remaining frequency content. Theimpedance vector disclosing the largest relative respiration componentis then used for PNS detection. During the template creation procedure,a PNS can be verified if the respiration content of an impedance signalwithin a time window during a refractory period of the left ventricle isabove a predetermined limit. The same impedance vector is accordinglyused as a reference to verify whether a PNS has occurred or for thetemplate creation for all impedance vectors.

According to embodiments of the present invention, different templatesare created for different postures and/or activity levels and/orstimulation vectors, i.e. electrode configurations used for delivery ofpacing pulses. This will improve the accuracy of the PNS detection sincethe impedance is sensitive to the posture of the patient. For example,the heart will shift position in the chest depending on whether thepatient lies in supine or stands or sits, which will result in slightlydifferent electrode configurations with respect to the heart and otherorgans. This will in turn affect the impedance signal morphology.Further, the location of the leads with respect to the phrenic nervewill also change with different posture, and thus the phrenic nervestimulation limit may also change. Thereby, by creating templates fordifferent postures and/or different activity levels and/or stimulationvectors, the accuracy of the PNS detection and PNS reduction can beenhanced.

According to embodiments of the present invention, tests or proceduresfor detecting PNS are regularly performed. The PNS test or PNS detectionprocedure is performed at regular intervals and/or at detection of aspecific posture and/or a specific activity level and/or at occurrenceof a predetermined hemodynamic event. The PNS test may include to:

-   -   deliver a pacing pulse having a predetermined amplitude/width        within a refractory period of the left ventricle, wherein pacing        pulses are repeatedly delivered during a number of cardiac        cycles;    -   measure impedance signals in time windows synchronized with the        delivery of pacing pulses in the refractory period of the left        ventricle using at least one electrode configuration;    -   gather at least one measured impedance signal from each time        window, and    -   analyze the gathered impedance signals to detect morphological        events and/or deviations indicating PNS by comparing the        gathered impedance signals with an impedance signal template.

In embodiments of the present invention, the hemodynamic events include,for example, an oxygen saturation of the blood being below apredetermined limit, a contractility being below a predetermined limit,blood pressure (e.g. left ventricle pressure changes) being below orabove predetermined limits or a heart sound (e.g. first heart sound, S1,and/or second heart sound, S2) indicating a change of the functioning ofthe heart. To this end, optical sensors can be used for sensing theoxygen saturation, accelerometers can be used to measure contractility,pressure sensors can be used to sense pressure and heart soundmicrophones can be used to measure the heart sounds. Changes or defectsin the electrode system, such as electrode displacements, interruptionsin leads, or isolation defects may lead to changes in the hemodynamics.These changes may affect the heart function, limit values and impedancemorphology.

According to embodiments of the present invention, a PNS threshold gapbetween a PNS threshold and a pacing therapy threshold is determined,wherein, at a PNS threshold gap being below a predetermined value, anadaptation of pacing settings of the implantable medical device isperformed. The adaptation of pacing settings may include changingelectrode configuration for delivery of pacing pulses and/or adaptingpacing energy and/or adapting pulse characteristics.

According to embodiments of the present invention, the PNS test includesmeasuring impedance signals in time windows synchronized with thedelivery of a pacing pulse in the refractory period of the leftventricle using more than one electrode configuration in a time windowor alternately using different electrode configurations for differenttime windows. Furthermore, at least one measured impedance signal isgathered from each time window and for each electrode configuration andthe gathered impedance signals for each electrode configuration arecompared with a corresponding impedance signal template for eachelectrode configuration and a PNS factor is applied for each electrodeconfiguration.

The absolute differences between each sample of the templates with PNSand the template without PNS are summed for each time window. The timewindow sums are then averaged over the applicable time windows. Thisshould be performed for each impedance configuration. Each average sum(Ai, i=index for impedance configuration) will then be multiplied with aPNS factor being separate for each impedance configuration. The value ofeach PNS factor is controlled by the following rule:A1*PNSfactor1=A2*PNSfactor2= . . . =Ak*PNSfactork

The steps above should be carried out for each body posture andactivity. When the impedance signals from each impedance configurationshall be combined as input to the PNS detection analysis, each impedancesignal shall be multiplied with the PNS factor belonging to respectiveimpedance configuration. If the PNS detection is carried out usingfrequency spectra the same procedures as above can be carried out usingthe frequency components in the selected frequency range instead of theimpedance signals. The calculated differences mentioned above are inthis case obtained by subtraction of each spectral component of thespectrum with and without PNS. According to embodiments of the presentinvention, combinations of impedance measurement vectors are used fordetecting PNS. At regular intervals and/or at detection of a specificposture and/or a specific activity level and/or at occurrence of apredetermined hemodynamic event the PNS test is performed. The pacingmodule repeatedly delivers pacing pulses within a refractory period ofthe left ventricle of the heart during a number of cardiac cycles, whichpacing pulses have a predetermined amplitude/width. The impedancemeasurement module measures impedance signals in time windowssynchronized with the delivery of a pacing pulse in the refractoryperiod of the left ventricle using more than one electrode configurationin a time window or alternately using different electrode configurationsfor different time windows. Further, the PNS detection module gathers atleast one measured impedance signal from each time window and for eachelectrode configuration and analyzes the gathered impedance signals todetect morphological events and/or deviations indicating PNS bycomparing the gathered impedance signals for each electrodeconfiguration with a corresponding impedance signal template for eachelectrode configuration and applying a PNS factor for each electrodeconfiguration.

In embodiments of the present invention, a difference waveform between ameasured impedance waveform and each corresponding template for eachelectrode configuration is calculated and a difference value for eachelectrode configuration is determined. Each difference value ismultiplied with the corresponding PNS factor to determine a resultingvalue for each electrode configuration, the resulting values for allelectrode configurations are added and is determined that PNS hasoccurred if the added resulting value is higher than a predetermined PNSthreshold.

According to embodiments of the present invention, a PNS factor iscalculated for each electrode configuration reflecting a differencebetween an impedance signal template with PNS content and an impedancesignal template without PNS content for that specific electrodeconfiguration. Alternatively, the PNS factor for each electrodeconfiguration reflect a difference between frequency content in animpedance waveform with PNS content and frequency content in animpedance waveform without PNS content.

According to embodiments of the present invention, a template (e.g. fora particular posture and/or activity level) can be created based onintrinsic data, i.e. impedance signals obtained during intrinsicactivity (without any pacing stimulation). Following an intrinsic leftventricular activation, the impedance can be recorded in time windowsstarting in the refractory period of the left ventricle. A template canbe created for each time window (based on recordings from several heartbeats) for that particular posture and/or activity level. One templatemay be created for that particular posture and/or activity level andtime window based on aggregated impedance recordings from a number ofcardiac cycles. A template (or templates) created according to thisprocedure will reflect impedance signals without PNS content.

In embodiments of the present invention, a template (e.g. for aparticular posture and/or activity level) can be created based onventricular stimulation, i.e. impedance signals resulting from pacingstimulation. Following a left ventricular activation, the impedance canbe recorded in time windows starting in the refractory period of theleft ventricle. A template can be created for each time window (based onrecordings from several heart beats) for that particular posture and/oractivity level. One template may be created for that particular postureand/or activity level and time window based on aggregated impedancerecordings from the number of cardiac cycles. The stimulation in theleft ventricle should not result in a PNS (in case templates without PNScontent is desired), which may be the case if the margin between thepacing energy and the PNS threshold is small. For example, the PNSthreshold can be determined and the pacing energy can be reduced belowthis threshold to secure that no PNS occurs.

According to embodiments of the present invention, a template (e.g. fora particular posture and/or activity level) can be created based onimpedance signals with PNS content resulting from a delivered PNS testpulse within the refractory period of the left ventricle. Preferably,the template is created from impedance data collected over a number ofheart beats, i.e. from a number of time windows. One PNS test pulse isdelivered during the refractory period of the left ventricle of eachheart beat. The impedance signals can be averaged over the heart beatsin order to remove disturbing signal content such as respirationvariations. Preferably, the delivered pacing energy is above a verifiedPNS threshold so as to secure that the pacing pulse results in PNS.

According to embodiments of the present invention, the template creationis more frequent during a period of time close to an implantation of thecardiac device. For example, templates can be created once a day duringthe period of time close to the implantation and then successively becreated less frequently during the course of time. The templates arepreferably created for different postures and different activity levels,and possibly also for different pacing and impedance vectors. However, astable electrode system, i.e. a system that has been implanted during arelatively long period of time, may require a more frequent update ofthe templates in certain situations. For example, the lead positionsrelative to the phrenic nerve may change over time, which may increasethe risk for PNS significantly. The electrode system should therefore bemonitored. One such monitoring method is to measure lead impedance and achange above a predetermined threshold may trigger a template creationprocedure. Another monitoring method is to measure QRS amplitudes and achange above a predetermined threshold may trigger a template creationprocedure. A further method is to monitor changes in the impedancevector's morphologies and a change above a predetermined threshold maytrigger a template creation procedure. Yet another way is to monitor thepacing threshold (of the heart) and an increase above a predeterminedthreshold may trigger a template creation procedure. These differentmethods for monitoring the electrodes can also be combined.

According to embodiments of the present invention, the control module isconfigured to instruct the pacing module to deliver the pacing pulses atthe different delays relative to the onset of the refractory period ofthe left ventricle in different cardiac cycles, wherein the onset of therefractory period of the left ventricle is determined to be a deliveryof a stimulation pulse resulting in a ventricle contraction or aspontaneous ventricle contraction.

According to embodiments of the present invention, the control module isconfigured to instruct the pacing module to deliver the pacing pulsesvia at least a first electrode configuration and wherein the impedancemeasurement module is configured to measure at least one impedancesignal using at least a second electrode configuration.

According to embodiments of the present invention, the control module isconfigured to perform a template creation procedure at predeterminedtime intervals or at receipt of an instruction.

According to embodiments of the present invention, the control module isconfigured to monitor changes in lead system criteria and, at detectionof a change in at least one lead system criteria exceeding apredetermined threshold, to perform a template creation procedure and/orinstruct the pacing module to change electrode configuration fordelivery of pacing pulses and/or to issue an alert. The lead systemcriteria indicates changes in the function of the lead system due to,for example, changes in the location of electrodes, changes in thefunctioning of electrodes, which, in turn affect the potential phrenicnerve stimulation, e.g. phrenic nerve stimulation threshold, or thegathering of impedance signals. Examples of such lead system criteriainclude, but are not limited to, lead impedance (electrode impedance),QRS amplitude, or QRS morphology.

According to embodiments of the present invention, the device furthercomprises a posture sensor configured to sense a posture of the patientand/or an activity sensor is configured to sense an activity level ofthe patient.

According to embodiments of the present invention, the control module isconfigured to perform a template creation procedure including:instructing the impedance measurement module to measure impedancesignals in time windows in the refractory period of the left ventricleat predetermined delays relative to the onset of the refractory periodof the left ventricle using at least one electrode configuration andinstructing the PNS detection module to create impedance signaltemplates using the gathered impedance signals. The control module isconfigured to two or several impedance signal templates in the PNSdetection.

According to embodiments of the present invention, the control module isconfigured to perform a template creation procedure including:instructing the pacing module to deliver at least one pacing pulsehaving a predetermined pulse amplitude and/or width in at least one timewindow within a refractory period of the left ventricle during a numberof cardiac cycles for at least one posture, wherein pacing pulses arerepeatedly delivered during a number of cardiac cycles, instructing theimpedance measurement module to measure impedance signals in timewindows synchronized with the delivery of pacing pulses in therefractory period of the left ventricle using at least one electrodeconfiguration; and instructing the PNS detection module to: gatherimpedance signals measured within the time windows of the cardiac cyclesfor the different postures and create signal templates for the at leastone posture using the gathered impedance signals. The control module isconfigured to use two or more impedance signal templates in the PNSdetection.

According to embodiments of the present invention, the control module isconfigured to perform a template creation procedure including:instructing the pacing module to deliver at least one pacing pulsehaving a predetermined pulse amplitude and/or width in at least one timewindow within a refractory period of the left ventricle during a numberof cardiac cycles at different activity levels, wherein pacing pulsesare repeatedly delivered during a number of cardiac cycles, instructingthe impedance measurement module to measure impedance signals in timewindows synchronized with the delivery of pacing pulses in therefractory period of the left ventricle using at least one electrodeconfiguration and instructing the PNS detection module to: gatherimpedance signals measured within the time windows of the cardiac cyclesfor at least the different activity levels and create impedance signaltemplates for each activity level using the gathered impedance signals.The control module is configured to use two or more impedance signaltemplates in the PNS detection.

According to embodiments of the present invention, the control module isconfigured to perform a template creation procedure including:instructing the pacing module to deliver at least one pacing pulsehaving a predetermined pulse amplitude and/or width in at least one timewindow within a refractory period of the left ventricle during a numberof cardiac cycles using different electrode configurations, whereinpacing pulses are repeatedly delivered during a number of cardiaccycles, instructing the impedance measurement module to measureimpedance signals in time windows synchronized with the delivery ofpacing pulses in the refractory period of the left ventricle using atleast one electrode configuration, and instructing the PNS detectionmodule to: gather impedance signals measured within the time windows ofthe cardiac cycles, and create impedance signal templates for eachelectrode configuration using the gathered impedance signals. Thecontrol module is configured to use two or more impedance signaltemplates in the PNS detection.

According to embodiments of the present invention, the PNS detectionmodule is configured to: receive a verification whether a PNS hasoccurred or not during the gathering of impedance signals, theverification being received from an extracorporeal unit via acommunication module of the implantable medical device, and determinewhether a created impedance signal template is a template with PNScontent or without PNS content depending on the received verification.

According to embodiments of the present invention, the PNS detectionmodule is configured to, during a template creation procedure, analyzethe gathered impedance signals to determine whether a PNS has occurredor not including: for each time window, calculating the frequencycontent of the impedance waveform, determining a frequency contentrelated to respiration, detecting that a PNS has occurred if thefrequency content related to respiration is above a predeterminedfrequency content threshold for a selected frequency range, anddetermining whether a created impedance signal template is a templatewith PNS content or without PNS content depending on whether a PNS wasdetected or not.

According to embodiments of the present invention, the control module isconfigured to, at regular intervals and/or at detection of a specificposture and/or a specific activity level and/or at occurrence of apredetermined hemodynamic event, perform a PNS test including:instructing the pacing module to deliver a pacing pulse having apredetermined pulse amplitude and/or width within a refractory period ofthe left ventricle, wherein pacing pulses are repeatedly deliveredduring a number of cardiac cycles, instructing the impedance measurementmodule to measure impedance signals in time windows synchronized withthe delivery of pacing pulses in the refractory period of the leftventricle using at least one electrode configuration, and instructingthe PNS detection module to: gather at least one measured impedancesignal from each time window, and analyze the gathered impedance signalsto detect morphological events and/or deviations indicating PNS bycomparing the gathered impedance signals with an impedance signaltemplate.

According to embodiments of the present invention, the control module isconfigured to instruct the PNS detection module to: gather at least onemeasured impedance signal from each time window, and analyze thegathered impedance signals to identify a first pulse amplitude and/orwidth above the pacing therapy threshold that do not cause PNS. Thecontrol module is configured to determine an adequate PNS threshold gapto be the difference between the identified pulse amplitude and/or widthand the pacing therapy threshold.

According to embodiments of the present invention, the control module isconfigured to initiate a PNS threshold test including instructing thepacing module to deliver a pacing pulse within a refractory period ofthe left ventricle of the heart, wherein pacing pulses are repeatedlydelivered during a number of cardiac cycles and wherein the pacingpulses having a successively changed pulse amplitude and/or width, andinstructing the impedance measurement module to measure impedancesignals in time windows synchronized with the delivery of pacing pulsesin the refractory period of the left ventricle using at least oneelectrode configuration, and instructing the PNS detection module to:gather at least one measured impedance signal from each time window, andanalyze the gathered impedance signals to detect morphological eventsand/or deviations indicating PNS by comparing the gathered impedancesignals with impedance signal templates to identify pulse amplitudesand/or widths that do not cause PNS. The control module is configured todetermine the maximum of the pulse amplitude and/or width that do notcause PNS to be a PNS threshold.

According to embodiments of the present invention, the control module isconfigured to determine a PNS threshold gap between a PNS threshold anda pacing therapy threshold, wherein the control module is configured to,at a PNS threshold gap being below a predetermined value, perform anadaptation of pacing settings.

According to embodiments of the present invention, the control module isconfigured to, at detection of PNS at pulse amplitudes and/or widthsbelow a predetermined threshold for a specific electrode configurationinstruct the pacing module to change electrode configuration fordelivery of pacing pulses and/or adapt pulse amplitudes and/or widths.

According to embodiments of the present invention, the control module isconfigured to search for another electrode configuration includingselection of an electrode configuration according to a predeterminedorder of a set of configurations for delivery of pacing pulses, instructthe pacing module to deliver a pacing pulse having a predetermined pulseamplitude and/or width within a refractory period of the left ventricleduring a number of cardiac cycles, wherein pacing pulses are repeatedlydelivered during a number of cardiac cycles, for each of the electrodeconfigurations, instruct the impedance measurement module to measureimpedance signals in time windows synchronized with the delivery ofpacing pulses in the refractory period of the left ventricle using atleast one electrode configuration, and instruct the PNS detection moduleto: gather impedance signals measured within the time windows of thecardiac cycles and analyze the gathered impedance signals to detectmorphological events or deviations indicating PNS by comparing thegathered impedance signals with impedance signal templates. The controlmodule is configured to select the electrode configuration for pacingstimulation that provides a predetermined PNS threshold gap.

According to embodiments of the present invention, templates without PNScontent are used in the PNS detection. In that case, the PNS detectionmodule is, when analyzing the gathered impedance signals to detect PNS,configured to: for each time window, subtract each impedance sample froma corresponding impedance sample of a selected impedance signal templateto obtain difference values (which preferably are absolute), process theabsolute difference values to create an aggregated value for the timewindows, compare the aggregated value with a predetermined limit basedon the template, and detect that a PNS has occurred if the aggregatedvalue is above the predetermined limit.

According to other embodiments of the present invention, templates withPNS content are used in the PNS detection. In that case, the PNSdetection module is, when analyzing the gathered impedance signals todetect PNS, configured to, for each time window, subtract each impedancesample from a corresponding impedance sample of a selected impedancesignal template to obtain difference values (which preferably areabsolute), process the absolute difference values to create anaggregated value for the time windows, compare the aggregated value witha predetermined limit based on the template, and detect that a PNS hasoccurred if the aggregated value is below the predetermined limit.

According to embodiments of the present invention templates without PNSare used and the PNS detection module is, when analyzing the gatheredimpedance signals to detect PNS, configured to, for each time window,cross-correlate an impedance signal during a time window with animpedance signal template for the corresponding time window to produce afirst cross-correlation result, for each time window, cross-correlate animpedance signal template with itself to produce a secondcross-correlation result, calculate a difference value for each timewindow between the first and second cross-correlation results, e.g. forthe peak values of the results, calculate a sum of all absolutedifference values, compare the sum with a predetermined limit value, anddetect that a PNS has occurred if the aggregated value exceeds thepredetermined limit value.

According to embodiments of the present invention templates with PNS areused and the PNS detection module is, when analyzing the gatheredimpedance signals to detect PNS, configured to, for each time window,cross-correlate an impedance signal during a time window with animpedance signal template for the corresponding time window to produce afirst cross-correlation result, for each time window, cross-correlate animpedance signal template with itself to produce a secondcross-correlation result, calculate a difference value for each timewindow between the first and second cross-correlation results, calculatea sum of all absolute difference values, compare the sum with apredetermined limit value, and detect that a PNS has occurred if theaggregated value is below the predetermined limit value.

According to embodiments of the present invention, the PNS detectionmodule is, when analyzing the gathered impedance signals to detect PNS,configured to, for each time window, determine a number of points in theimpedance waveform where a derivative of the impedance waveform shows achange of sign, wherein a new sign of the derivative lasts apredetermined period of time, and detect that a PNS has occurred if adifference between a determined number of points and a reference numberof points is higher than or equal to a predetermined limit value.

According to embodiments of the present invention, the PNS detectionmodule is, when analyzing the gathered impedance signals to detect PNS,configured to, for each time window, calculate the frequency content ofthe impedance waveform, compare the calculated frequency content with afrequency content of selected impedance templates, and detect that a PNShas occurred if a deviation between the calculated frequency content andthe frequency content of the selected impedance templates is above apredetermined frequency content threshold for a selected frequencyrange.

According to embodiments of the present invention, the control module isconfigured to, at regular intervals and/or at detection of a specificposture and/or a specific activity level and/or at occurrence of apredetermined hemodynamic event, initiate a PNS test includinginstructing the pacing module to repeatedly deliver pacing pulses withina refractory period of the left ventricle of the heart during a numberof cardiac cycles, the pacing pulses having a predetermined pulseamplitude and/or width, and instructing the impedance measurement moduleto measure impedance signals in time windows synchronized with thedelivery of a pacing pulse in the refractory period of the leftventricle using more than one electrode configuration in a time windowor alternately using different electrode configurations for differenttime windows, instructing the PNS detection module to gather at leastone measured impedance signal from each time window and for eachelectrode configuration, and analyze the gathered impedance signals todetect morphological events and/or deviations indicating PNS bycomparing the gathered impedance signals for each electrodeconfiguration with a corresponding impedance signal template for eachelectrode configuration and applying an PNS factor for each electrodeconfiguration.

According to embodiments of the present invention, the PNS detectionmodule is, so as to detect morphological events and/or deviationsindicating PNS, configured to calculate a difference waveform between ameasured impedance waveform and each corresponding template for eachelectrode configuration, determine a difference value for each electrodeconfiguration, multiply each difference value with the corresponding PNSfactor to determine a resulting value for each electrode configuration,add the resulting values for all electrode configurations, and detectthat PNS has occurred if the added resulting value is higher than apredetermined PNS threshold.

According to embodiments of the present invention, the phrenic nervestimulation, PNS, detection module is configured to calculate a PNSfactor for each electrode configuration as reflecting a differencebetween an impedance signal template with PNS content and an impedancesignal template without PNS content for that specific electrodeconfiguration.

According to embodiments of the present invention, the control module isconfigured to instruct the pacing module to deliver pacing pulses havingpredetermined energies within a refractory period of the left ventricle,wherein pacing pulses are repeatedly delivered during a number ofcardiac cycles, wherein the impedance measurement module is configuredto measure impedance signals in time windows synchronized with thedelivery of pacing pulses in the refractory period of the left ventricleusing more than one electrode configuration simultaneously oralternately using different electrode configurations for different timewindows. The PNS detection module is configured to gather at least oneimpedance signal from each time window and for each electrodeconfiguration, calculating a PNS factor for each electrode configurationreflecting a difference between frequency content in an impedancewaveform with PNS content and frequency content in an impedance waveformwithout PNS content.

Further objects and advantages of the present invention will bediscussed below by means of exemplifying embodiments.

These and other features, aspects and advantages of the invention willbe more fully understood when considered with respect to the followingdetailed description, appended claims and accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are not necessarily drawn to scale and illustrategenerally, by way of example, but no way of limitation, variousembodiments of the present invention. Thus, exemplifying embodiments ofthe invention are illustrated by way of example and not by way oflimitation in the figures of the accompanying drawings in which likereferences indicate similar elements. It should be noted that referencesto “an” or “one” embodiment in this discussion are not necessarily tothe same embodiment, and such references mean at least one.

FIG. 1 is a simplified functional block diagram of one embodiment of animplantable medical device in accordance with the present invention,illustrating basic elements of the system;

FIG. 2 is a simplified and schematic diagram of one embodiment of asystem configuration according to the present invention including animplantable stimulation device in electrical communication with severalleads implanted in a patient's heart for detecting cardiac activity andfor delivering multi-chamber stimulation;

FIG. 3 schematically illustrates various waveforms including ECG andimpedance waveforms without PNS content during successive cardiaccycles;

FIG. 4 schematically illustrates various waveforms including ECG andimpedance waveforms with PNS content during successive cardiac cycles;

FIG. 5 is a flow chart illustrating steps in a method for creatingtemplates without PNS content;

FIG. 6 schematically illustrates ECG, IEGM and impedance signals duringa template creation procedure for creating templates without PNS contentusing stimulation;

FIG. 7 schematically illustrates ECG, IEGM and impedance signals duringa template creation procedure for creating templates without PNS contentusing stimulation based on intrinsic ventricular contractions;

FIG. 8 is a flow chart illustrating steps in a method for creatingtemplates with PNS content;

FIG. 9 schematically illustrates ECG, IEGM and impedance signals duringa template creation procedure for creating templates with PNS content;

FIG. 10 a-10 c schematically illustrates PNS detection based on waveformcomparison using templates without PNS content;

FIG. 11 a-11 c schematically illustrates PNS detection based on waveformcomparison using templates with PNS content;

FIG. 12 schematically illustrates PNS detection based on morphologyanalysis; and

FIG. 13 is a flow chart illustrating steps in a method for PNS detectionusing cross-correlation between template and impedance signals.

DESCRIPTION OF EXEMPLIFYING EMBODIMENTS

The following is a description of exemplifying embodiments in accordancewith the present invention. This description is not to be taken inlimiting sense, but is made merely for the purposes of describing thegeneral principles of the invention. It is to be understood that otherembodiments may be utilized and structural and logical changes may bemade without departing from the scope of the present invention. Forexample, embodiments may be used with a pacemaker, a cardioverter, adefibrillator, and the like.

Systems, devices and methods according to the present invention mayinclude one or more of the features, structures, methods, orcombinations thereof described herein. For example, a device or systemmay be implemented to include one or more of the advantageous featuresand/or processes described below in various different embodiments. It isintended that such a device or system need not include all of thefeatures described herein, but may be implemented to include selectedfeatures that provide for useful structures and/or functionality. Such adevice or system may be implemented to provide a variety of therapeuticor diagnostic functions.

A wide variety of implantable monitoring and/or stimulation devices maybe configured to implement phrenic nerve stimulation detection andphrenic nerve stimulation reduction according to the present invention.A non-limiting representative list of such devices includes cardiacmonitors, pacemakers, cardioverters, defibrillators, resynchronizers,and other cardiac monitoring and therapy delivery devices. These devicesmay be configured with different electrode arrangements includingtransvenous, endocardial, and epicardial electrodes. In multi-electrodepacing systems, multiple electrodes may be disposed in a single heartchamber, in multiple heart chambers, and/or elsewhere in a patient'sbody. Typically, pacing energy is delivered to the heart via cathodeelectrode(s) at one or more pacing sites, with a return path providedvia anode electrode(s). If cardiac capture occurs, the injected energycreates a propagating wavefront of depolarization to trigger acontraction of the cardiac muscle.

In FIG. 1, an exemplary, simplified block diagram depicting variouscomponents of the cardiac stimulator according to embodiments of thepresent invention is shown. The cardiac stimulator 10 is capable ofdelivering cardiac therapy via different electrode pairs and isconfigured to integrate both monitoring and therapy features, as will bedescribed below. Further, the cardiac stimulator 10 is capable ofcollecting and processing data about the heart 12 (see FIG. 2) fromelectrode pairs for sensing cardiac electrogram (EGM) signals and/orintracardiac or transthoracic impedance. While a particularmulti-chamber device is shown, it is to be appreciated and understoodthat this is done for illustration purposes only. Thus, the techniquesand methods described below can be implemented in connection with anysuitable configured or configurable stimulation device. Accordingly, oneof skill in the art could readily duplicate, eliminate, or disable theappropriate circuitry in any desired combination to provide a devicecapable of treating the appropriate chamber with pacing stimulation.

The cardiac stimulator 10 has a housing 40, often referred to as the“can” or “case electrode”. The housing 40 may function as a returnelectrode in “unipolar” modes. Further, the housing 40 includesconnector (not shown) having a plurality of terminals (not shown) forconnection with electrodes and/or sensors.

The cardiac stimulator 10 includes a programmable microcontroller orcontrol module 51 that inter alia controls the various modes ofstimulation therapy. As is well known within the art, themicrocontroller 51 typically includes a microprocessor, or equivalentcontrol circuitry, designed specifically for controlling the delivery ofstimulation therapy and may further include RAM or ROM memory, logic andtiming circuitry, state machine circuitry, and I/O circuitry. Typically,the microcontroller 51 includes the ability to process or monitor inputsignals (data or information) as controlled by a program stored in adesignated block of memory. The type of microcontroller is not criticalto the described implementations. Rather, any suitable microcontroller51 may be used that carries out the functions described herein. The useof micro-processor based control circuits for performing timing and dataanalysis are well known in the art.

Furthermore, the cardiac stimulator 10 includes pacing module 52 adaptedto provide pacing signals for delivery to the patient. The pacing module52 comprises an atrial pulse generator 53 and a ventricular pulsegenerator 54 that generate pacing stimulation pulses for delivery byleads 14, 16, and 18 via an electrode configuration switch 55. In FIG.2, an embodiment including a right atrial lead 14, a coronary sinus lead16, and a right ventricular lead 18 is shown.

It is understood that in order to provide stimulation therapy in each ofthe four chambers, the atrial and ventricular pulse generators 53 and54, may include dedicated, independent pulse generators, multiplexedpulse generators, or shared pulse generators. The pulse generators 53and 54 are controlled by the microcontroller 51 via appropriate controlsignals to trigger or inhibit stimulation pulses.

A cardiac data recording module 62 is configured to collect, forexample, cardiac signals such as IEGM signals and, if required, recordthe cardiac signals. The cardiac data recording module 62 may for thispurpose interact with an ECG unit (not shown) that provides electricalimpulses or other observed signals that can be used to, for example,monitor the patient's ECG waveform. Based on the IEGM signals, the onsetof the refractory period of the left ventricle can be determined, whichinformation can be used in the PNS detection.

A data collecting module 64 is configured to collect measurementcondition information corresponding to, for example, activity levelinformation of the patient and/or body posture information.

The data collecting module 64 suitably interacts with one or more dataproviding units or sensors 70 to obtain data about the patient such asactivity level or body posture. The data providing units 70 include, forexample, an accelerometer.

An impedance measuring module 66 is configured to measure, for example,intracardiac impedance and/or transthoracic impedance via electrodes ofthe medical leads 14, 16, and 18 and/or the can. The impedance measuringmodule 66 may comprise a voltage measuring circuit (not shown) formeasuring a voltage via the electrode configuration switch 55 andelectrodes arranged in the medical leads (e.g. over LV tip electrode 75and LV ring electrode 76 a or over LV ring electrodes 76 b and 76 c, seeFIG. 2).

Further, the impedance measuring module 66 may also include a currentinjection circuit (not shown) for injecting current via the electrodeconfiguration switch 55 and electrodes arranged in the medical leads(e.g. over LV tip electrode 75 and LV ring electrode 76 a or over LVring electrodes 76 b and 76 c, see FIG. 2).

Control signals from the microcontroller 51 determine, for example, whenthe cardiac data recording module 62 and/or data collecting module 64and/or impedance measuring module 66 collects signals, stores them inthe memory or transmit them to a phrenic nerve stimulation, PNS,detection module 60.

The cardiac data recording module 62 and the impedance measuring module66 are coupled to the right atrial lead 14, the coronary sinus lead 16,and the right ventricular lead 18 to sample cardiac signals across anycombination of electrodes.

The microcontroller 51 includes timing control circuitry 56 to controltiming of the stimulation pulses (e.g. pacing rate, AV delay, VV delay,etc.) as well as to keep track of timing of refractory periods blankingintervals, etc., which is well known in the art. In addition, themicrocontroller 51 may include components such as e.g. an arrhythmiadetector (not shown). Furthermore, the timing control circuitry 56controls the selection of electrode configuration, i.e. pacing sites,used for delivering the stimulation pulses.

Furthermore, the microcontroller 51 is coupled to a memory 49 by asuitable data/address bus (not shown), wherein the programmableoperating parameters used by the microcontroller 51 are stored andmodified, as required, in order to customize the operation of thecardiac stimulator to the needs of a particular patient. Such operatingparameters define, for example, pacing pulse amplitude, pulse duration,etc.

Advantageously, the operating parameters may be non-invasivelyprogrammed into the memory 49 through a communication module 59including, for example, a telemetry circuit for telemetric communicationvia communication link 63 with an external device 68, such as aprogrammer or a diagnostic system analyzer. The telemetry circuit 59advantageously allows intracardiac electrograms and status informationrelating to the operation of the device 10 to be sent to the externaldevice 68 through an established communication link 63. Further, thecommunication module may alternatively or as a complement to thetelemetry circuit include circuits for RF communication.

Moreover, the cardiac stimulator 10 additionally includes a battery 65that provides operating power to all of the circuits shown in FIG. 1.Preferably, the stimulator 10 employs lithium or similar batterytechnology.

The PNS detection module 60 is configured to detect PNS by analyzingexcursions or deviations of impedance signals caused by PNS. Theexcursions or deviations are identified in recorded impedance signals bycomparison with templates, preferably different templates for differentpostures and/or activity levels of the patient as well as for differentmeasurement vectors. Further, templates with PNS content as well astemplates without any PNS content may be used in the PNS detection.

The present invention is based on the insight that the PNS causedexcursion or deviation moves in time in synchronism with the stimulationpulse delivered to the left ventricle, which can be utilized to increasethe accuracy of the PNS detection. The pace pulses are delivered to theleft ventricle inside the refractory period of the left ventricle.Simultaneously with the stimulation pulse a time window is started thatis broad enough to capture the PNS caused excursions or deviations.Further, the stimulation pulses are delivered with different timingsrelative to the onset of the refractory period of the left ventricle andsince the time windows are synchronized with the stimulation pulses, thetime windows will move from beat to beat relative to the onset of therefractory period of the left ventricle. The impedance signals arerecorded within the time windows and are collected beat by beat. This isillustrated in FIG. 4 and is discussed in more detail below.

The aforementioned component or components of the microcontroller 51 maybe implemented as part of the microcontroller 51, or assoftware/firmware instructions programmed into the device and executedon the microcontroller 51 during certain modes of operation.

With reference to FIG. 2, one implementation of a system according tothe present invention including an implantable cardiac stimulator asdescribed in FIG. 1 connectable to one or more medical leads will bediscussed. As the skilled person realizes, the system implementationshown in FIG. 2 is only exemplary.

The implantable cardiac stimulator 10 is in electrical communicationwith a patient's heart 12 by way of three leads 14, 16, and 18 suitablefor delivering multi-chamber stimulation therapy.

To sense atrial signals and to provide right atrial chamber stimulationtherapy, the stimulator 10 is coupled to an implantable right atriallead 14 having, for example, an atrial tip electrode 71, which typicallyis implanted in the patient's right atrial appendage or septum. FIG. 2shows the right atrial lead 14 as also having an atrial ring electrode72.

The cardiac stimulator 10 is in electrical communication with the heart12 by way of an implantable right ventricular lead 18 having, in thisembodiment, a right ventricular tip electrode 73 and right ventricularring electrodes 74 a-74 c. Typically, the right ventricular lead 18 istransvenously inserted into the heart 12 to place the right ventriculartip electrode 73 in the right ventricular apex. The right ventricularlead 18 is capable of sensing or receiving cardiac signals, anddelivering stimulation in the form of pacing therapy.

The cardiac stimulator 10 may further sense left atrial and ventricularcardiac signals and provide left chamber pacing therapy via the coronarysinus lead 16 designed for placement in the coronary sinus region viathe coronary sinus for positioning a distal electrode adjacent to theleft ventricle and/or additional electrode(s) adjacent to the leftatrium. As used herein, the phrase “coronary sinus region” refers to thevasculature of the left ventricle, including any portion of the coronarysinus, great cardiac vein, left marginal vein, left posteriorventricular vein, middle cardiac vein, and/or small cardiac vein or anyother cardiac vein accessible via the coronary sinus.

The coronary sinus lead 16 is designed to receive atrial and ventricularpacing signals and to deliver left ventricular pacing therapy using, forexample, a left ventricular tip electrode 75 and left ventricular ringelectrodes 76 a-76 c, and deliver left atrial pacing therapy using aleft atrial ring electrode 24.

In operation, the cardiac stimulator 10 obtains data about the heart 12via the leads 14, 16 and 18 and possibly via other data providing units.This data is provided to the internal processor 51 (see FIG. 1), whichanalyses the data and provides a response as appropriate. In particular,the cardiac stimulator 10 generates one or more therapy signals that arepreferably optimized in accordance with the obtained data.

As has been discussed above, left ventricular pacing via the leftventricular lead 16, placed via the coronary sinus, using the electrodes75, 76 a-76 c, may cause undesired phrenic nerve stimulation due to theproximity of the coronary veins to the phrenic nerve. Unintendedactivation of the phrenic nerve via a cardiac pacing pulse can beuncomfortable for the patient, and can interfere with breathing.Therefore, phrenic nerve activation from cardiac pacing may cause thepatient to exhibit uncomfortable breathing patterns timed with leftventricular pace. In FIGS. 3 and 4, respectively, the impedance signalmorphology following a ventricular pace without PNS (FIG. 3) and withPNS (FIG. 4) is schematically illustrated.

In FIG. 3, an impedance signal, Z, without any undesired phrenic nervestimulation is illustrated over two consecutive cardiac cycles. As canbe seen, the impedance signal, Z, varies with the ECG signal. Therefractory period 300 for the left ventricle, V_(ref), is shown for thesuccessive cardiac cycles. As can be seen in FIG. 4, the impedancesignal Z will demonstrate significant morphological excursions ordeviations caused by the PNS compared to the non-PNS impedance signalshown in FIG. 3. Hence, if a PNS has occurred there exist PNS footprintsin the impedance signals that can be used for the PNS detection.

In FIG. 4, the principles of the present invention including delivery ofa pacing pulse in the refractory period of the left ventricle, recordingthe impedance in a time window following the pacing pulse and displacingthe time windows relative each other in different cardiac cycles areshown. In this illustrated example, the pacing pulse is delivered in therefractory period of the left ventricle and the impedance signal isrecorded in time windows of four consecutive cardiac cycles. However, itis not necessary to use consecutive cardiac cycles for the phrenic nervestimulation detection, for example, every second cardiac cycle or everythird cardiac cycle may instead be used.

In this illustrated case, pace pulses are delivered to the leftventricle in the refractory period 400 of the left ventricle. Thedelivery of each pace pulse initiates a respective time window 401 a-401d having a length of about 100-150 ms and the impedance signal isrecorded within these time windows. In the illustrated example, thedelivery of a pace pulse triggers a phrenic nerve stimulation, which isreflected in the impedance signal by the irregularities or peaks 402a-402 d. According to the present invention, the impedance signals ofthe time windows can be aggregated, for example, a sum impedance signalor an average impedance signal can be created to improve the detectionof the phrenic nerve stimulation footprint in the impedance signal.

With reference now to FIG. 5-9, different approaches for creatingtemplates will be discussed.

FIGS. 5 and 8 are flow diagrams of processes according to embodiments ofthe present invention. The various tasks performed in connection withthe processes may be performed by software, hardware, firmware, or anycombination thereof. For illustrative purposes, the followingdescription of the processes refers to elements mentioned above inconnection with FIGS. 1 and 2. In practical embodiments, portions of theprocesses may be performed by different elements of the describedcardiac stimulator. It should be appreciated that the processes mayinclude any number of additional or alternative tasks or steps, thetasks shown in FIGS. 5 and 8 need not be performed in the illustratedorder, and the processes may be incorporated into a more comprehensiveprocedure or process having additional functionality not described indetail herein.

With reference first to FIGS. 5-7, acquisition of templates without PNScontent will be discussed. In FIG. 5, a flow chart describing stepsexecuted when acquiring templates without PNS content is shown and inFIGS. 6 and 7 signals and time windows used for the creation oftemplates without PNS content are schematically illustrated. The atrialcontraction may be intrinsic or pace activated. The illustratedsituation concerns a patient having left bundle block, which can be seenfrom a broadened QRS-complex and a delay between the right ventricle andleft ventricle.

In FIGS. 6 and 7, a number of possible time windows W1 _(int)-Wn_(int),for template creation within the left ventricle's refractory period areshown. Each time window will have a template, created from correspondingtime windows from several cardiac cycles, for example, an average overseveral cardiac cycles. Further, a template is additionally preferablycreated for each posture and activity level. The templates can becreated based on impedance measurements during a left ventriclerefractory period following an intrinsic left ventricle activation orfollowing a delivery of a stimulation pulse as shown in FIG. 6 and FIG.7, respectively.

In order to create the template without PNS content according to thisembodiment, an LV electrode for template building is first selected instep S500 of the process 100. Posture and/or activity level may also beselected or determined before the actual template creation procedure isinitiated. At step S510, a list of delays, Tdelay(1)-Tdelay(n) (see FIG.6), are created for later PNS detection using a PNS test pulse. Thedelays Tdelay(1)-Tdelay(n) define the starting point of the time windowsW1 _(int)-Wn_(int) from the onset of the refractory period of the leftventricle, which can be initiated by an intrinsic ventricularcontraction or a delivery of a stimulation pulse.

In this example, the delay Tdelay1 is zero for the first time window W1_(int). Each delay is related to the first stimulation pulse (to createa ventricular contraction) or at detection of a QRS. The starting pointsof the windows W1 _(int.)-Wn_(int) should be distributed over the leftventricular refractory period.

At step S520, the right ventricle is stimulated to start a contractionand create refractory left ventricular tissue if no spontaneousventricular contraction is detected. Thereafter, at step S530, theimpedance signal is collected during a period covering all time windowsW1 _(int.)-Wn_(int) following the stimulation pulse or the spontaneouscontraction. Steps S520 and S530 are preferably repeated for a number ofheart cycles.

Then, at step S540, it is checked whether impedance signals for apredetermined number of heart cycles have been collected. If no, theprocess returns to step S520. If yes, the process proceeds to step S550,where a template for selected time windows or for each time window W1_(int.)-Wn_(int) is created, for example, by extracting data from anaverage impedance signal based on all collected impedance signalsaccording to the specific Tdelay and time window width.

Turning now to FIGS. 8 and 9, acquisition of templates with PNS contentwill be discussed. In FIG. 8, a flow chart describing steps executedwhen acquiring templates with PNS content is shown and in FIG. 9,signals during creation of templates based on impedance signals with PNScontent are schematically illustrated.

The atrial contraction may be intrinsic or pace activated. Each timewindow within the left ventricle refractory period will have a template,created from corresponding time windows from several cardiac cycles, forexample, an average over several cardiac cycles. Further, a template isadditionally preferably created for each posture and activity level. Thetemplates can be created based on impedance measurements during a leftventricle refractory period following intrinsic left ventricleactivation or following a delivery of a stimulation pulse.

In order to create the template with PNS content according to thisembodiment, an LV electrode for template building is first selected instep S700 of the process 200. Posture and/or activity level may also beselected or determined before the actual template creation procedure isinitiated. A pulse amplitude and/or width being sufficient for PNSshould be applied in the following template creation procedure. In orderto secure phrenic nerve capture, an extra margin may be added to the PNSpulse amplitude and/or width threshold.

At step S710, a list of delays, Tdelay(1)-Tdelay(n), are created forlater PNS detection using a PNS test pulse. The delaysTdelay(1)-Tdelay(n) define the starting point of the time windowsW(1)-W(n) from the onset of the refractory period of the left ventricle,which can be initiated by an intrinsic ventricular contraction or adelivery of a stimulation pulse.

In this example, the delay Tdelay(1) is zero for the first time windowW(1). Each delay is related to the first stimulation pulse (to create aventricular contraction) or the detection of a QRS. The starting pointsof the time windows W(1)-W(n) should be distributed over the leftventricular refractory period.

At step S720, a first delay(j), j=1, for the start of the time windowW(j) is selected for template creation.

At step S730, a stimulation pulse in the right ventricle is delivered tostart a contraction and create refractory left ventricular tissue.

Thereafter, a PNS test pulse is delivered after Tdelay(j) in the leftventricle at step S740.

At step S750, the impedance signal is collected during the time windowW(j) for a heart cycle.

Thereafter, in step S760, it is checked whether impedance signals havebeen collected for a predetermined number of heart cycles. If no, theprocedure returns to step S730. If yes, the procedure proceeds to stepS770 where a template for time window W(j) is created based on thecollected impedance signals during the predetermined number of heartcycles.

At step S780, it is checked whether templates have been created for alldelays, Tdelay(1)-Tdelay(n), and if not, the procedure proceeds first tostep S790 and then to step S720 where j is set to j=j+1, and the delayaccordingly is set to Tdelay(j=j+1), respectively. Then, steps S730-S770are repeated to create a template for the time window W(j=j+1). On theother hand, if it is verified in step S780 that a template has beencreated for all delays, Tdelay(1)-Tdelay(n), it is concluded in stepS800 that templates for all delays Tdelay(1)-Tdelay(n) and respectivetime windows W(1)-W(n) have been created and the template creationprocess can be finished.

With reference now to FIGS. 10 a-10 c, and 11 a-11 c, analysis ofimpedance signal content to detect PNS will be discussed.

In FIGS. 10 a-10 c, templates without PNS content and signal comparisonto detect PNS is illustrated, respectively. In FIGS. 11 a-11 c,templates with PNS content and signal comparison to detect PNS isillustrated, respectively. In these examples (as particularly shown inFIGS. 10 b, 10 c, 11 b and 11 c), the actual impedance signal waveformsare compared with the impedance signal waveforms of the templates toidentify whether PNS is present (FIGS. 10 b and 11 c) or not (FIGS. 10 cand 11 b) in the actual impedance signals.

If templates without PNS content are used as shown in FIG. 10 a-10 c, atotal difference area, i.e. the sum of A₁−A_(n), between the actualimpedance signals and the templates being larger than a predeterminedlimit will indicate that PNS has occurred as can be seen in FIG. 10 b.However, if the total difference area, i.e. the sum of A′₁−A′_(n),between the actual impedance signals and the templates is smaller thanthe predetermined limit it is an indication that the actual impedancesignals do not include PNS content, as can be seen in FIG. 10 c.

Turning now to FIG. 11 a-11 c where it is illustrated how the comparisonmay be performed when templates with PNS content are being used. In thiscase, a total difference area, i.e. the sum of A₁−A_(n), between theactual impedance signals and the templates being larger than apredetermined limit will indicate that a PNS has not occurred, as can beseen in FIG. 11 b. However, if the total difference area, i.e. the sumof A′₁−A′_(n), between the actual impedance signals and the templates issmaller than the predetermined limit it is an indication that the actualimpedance signals include PNS content, as can be seen in FIG. 11 c.

With reference now to FIG. 12, a method for analyzing impedancemorphology to identify PNS will be discussed. The effects on theimpedance signals due to PNS are shown in FIG. 12 and in this examplethe number of times a filtered impedance signal crosses upper and lowerpredetermined levels is used for PNS detection. At presence of PNS, thenumber of level crossings will increase. As reference, the number oflevel crossing when no PNS is at hand and the number of level crossingsat presence of PNS are counted. The predetermined upper and lower levelsare set so there is a difference between the two cases. For example, iftwo or more level crossings occur it is determined that PNS hasoccurred. In FIG. 12, a PNS is detected since four level crossings areidentified.

According to embodiments of the present invention, PNS detection usingfrequency spectrum can also be made. The lungs are expected to changequickly in size at a PNS event. This creates higher frequency componentsin the impedance signal spectrum. Spectral components will appear in thespectrum at a higher frequency range. The detection of PNS can be madeby calculating the area under the obtained frequency spectrum. This areacan be compared to an area calculated using a frequency spectrumobtained with and/or without PNS

With reference now to FIG. 13, an exemplary embodiment of the presentinvention for detecting PNS using cross-correlation will be discussed.FIG. 13 illustrates a flow chart describing tasks or steps performed todetect PNS using cross-correlation. The various tasks described in FIG.13 performed in connection with the processes may be performed bysoftware, hardware, firmware, or any combination thereof. Forillustrative purposes, the following description of the processes refersto elements mentioned above in connection with FIGS. 1 and 2. Inpractical embodiments, portions of the processes may be performed bydifferent elements of the described cardiac stimulator. It should beappreciated that the processes may include any number of additional oralternative tasks or steps, the tasks shown in FIG. 13 need not beperformed in the illustrated order, and the processes may beincorporated into a more comprehensive procedure or process havingadditional functionality not described in detail herein.

In step S800, a counter for the window W(i) is set to i=1. At step S810,a cross-correlation process is performed with the template from W(i) andthe obtained impedance signals from the window W(i). Then, at step S820,a cross-correlation process is performed with the template from W(i) anditself. The results from the cross-correlation procedures are stored ina respective vector M1 and M0, respectively. At step S830, center valuesfor the vectors M1 and M0 are determined:m1c=M1(center)m0c=M0(center)

Thereafter, at step S840, the absolute difference between m1c and m0c iscalculated:Delta(i)=abs(m1c−m0c)

At step S850, it is checked whether all windows have been evaluated inthe cross-correlation procedure 300. If not, the procedure 300 proceedsto step S860 where the counter is set to i=i+1. Then, the procedure 300returns to steps S810-S850. On the other hand, if all windows have beenevaluated, the procedure 300 proceeds to step S870 where all absolutedifference components are summed:Delats_sum=sum(delta)

In step S880, the sum is compared to a predetermined test limit. Thetest criteria will depend on whether a template with or without PNS isused. If a template without PNS is used, a sum exceeding the test limitwill indicate presence of PNS and a sum being below the test limit willindicate that no PNS is present and, inversely, if a template with PNSis used, a sum being below the test limit will indicate presence of PNSand a sum exceeding the test limit will indicate that no PNS is present.In the embodiment illustrated in FIG. 13, a template without PNS contentis used. Hence, if the sum exceeds the predetermined test limit in thecomparison performed in step S880, the procedure 300 proceeds to stepS890 where it is determined that PNS has been detected. On the otherhand, if the sum is below the predetermined test limit, the procedure300 proceeds to step S900 where it is determined that no PNS has beendetected.

In embodiments of the present invention, the impedance signals/frequencycontent obtained from different electrode configurations are merged orweighted with a respective PNS factor, which is based on a differencebetween a template with PNS content and a template without PNS content.The absolute differences between each sample of the templates with andthe template without PNS are summed for each time window. The timewindow sums are then averaged over the applicable time windows. Thisshould be performed for each impedance configuration. Each average sum(Ai, i=index for impedance configuration) will then be multiplied with aPNS factor, being separate for each impedance configuration. The valueof each PNS factor is controlled by the following rule:A1*PNSfactor1=A2*PNSfactor2= . . . =Ak*PNSfactork

The steps above should be carried out for each body posture andactivity. When the impedance signals from each impedance configurationshall be combined as input to the PNS detection analysis, each impedancesignal shall be multiplied with the PNS factor belonging to respectiveimpedance configuration. If the PNS detection is carried out usingfrequency spectra the same procedures as above can be carried out usingthe frequency components in the selected frequency range instead of theimpedance signals. The calculated differences mentioned above are inthis case obtained by subtraction of each spectral component of thespectrum with and without PNS.

According to embodiments of the present invention, the PNS test includesmeasuring impedance signals in time windows synchronized with thedelivery of a pacing pulse in the refractory period of the leftventricle using more than one electrode configuration in a time windowor alternately using different electrode configurations for differenttime windows. Furthermore, at least one measured impedance signal isgathered from each time window and for each electrode configuration andthe gathered impedance signals values for each electrode configurationare compared with a corresponding impedance signal template for eachelectrode configuration and a PNS factor is applied for each electrodeconfiguration.

According to embodiments of the present invention, combinations ofimpedance measurement vectors are used for detecting PNS. At regularintervals and/or at detection of a specific posture and/or a specificactivity level and/or at occurrence of a predetermined hemodynamic eventthe PNS test is performed. The pacing module repeatedly delivers pacingpulses within a refractory period of the left ventricle of the heartduring a number of cardiac cycles, which pacing pulses have apredetermined amplitude/width. The impedance measurement module measuresimpedance signals in time windows synchronized with the delivery of apacing pulse in the refractory period of the left ventricle using morethan one electrode configuration in a time window or alternately usingdifferent electrode configurations for different time windows. Further,the PNS detection module gathers at least one measured impedance signalfrom each time window and for each electrode configuration and analyzesthe gathered impedance signals to detect morphological events and/ordeviations indicating PNS by comparing the gathered impedance signalsfor each electrode configuration with a corresponding impedance signaltemplate per time window for each electrode configuration and applying aPNS factor for each electrode configuration.

In embodiments of the present invention, a difference waveform between ameasured impedance waveform and each corresponding template for eachelectrode configuration is calculated and a difference value for eachelectrode configuration is determined. Each difference value ismultiplied with the corresponding PNS factor to determine a resultingvalue for each electrode configuration, the resulting values for allelectrode configurations are added and it is determined that PNS hasoccurred if the added resulting values are higher than a predeterminedPNS threshold.

According to embodiments of the present invention, a PNS factor iscalculated for each electrode configuration reflecting a differencebetween an impedance signal template with PNS content and an impedancesignal template without PNS content for that specific electrodeconfiguration. Alternatively, the PNS factor for each electrodeconfiguration reflects a difference between frequency content in animpedance waveform with PNS content and frequency content in animpedance waveform without PNS content.

Although certain embodiments and examples have been described herein, itwill be understood by those skilled in the art that many aspects of thedevices and methods shown and described in the present disclosure may bedifferently combined and/or modified to form still further embodiments.Alternative embodiments and/or uses of the devices and methods describedabove and obvious modifications and equivalents thereof are intended tobe within the scope of the present disclosure. Thus, it is intended thatthe scope of the present invention should not be limited by theparticular embodiments described above, but should be determined by afair reading of the claims that follow.

The invention claimed is:
 1. An implantable medical device connectableto a plurality of electrodes electrically coupled to a heart of apatient in at least one electrode configuration, comprising: a pacingmodule configured to deliver pacing pulses to the heart using said atleast one electrode configuration; a control module configured toinstruct said pacing module to deliver pacing pulses having apredetermined pulse amplitude and/or width within the refractory periodof the left ventricle, wherein said pacing pulses are repeatedlydelivered during a number of cardiac cycles and wherein said pacingpulses are delivered at different predetermined delays relative to anonset of the refractory period of the left ventricle in differentcardiac cycles; an impedance measurement module configured to measureimpedance signals in time windows synchronized with said delivery ofpacing pulses in said refractory period of the left ventricle using atleast one electrode configuration; a phrenic nerve stimulation, PNS,detection module configured to: gather at least one impedance signalfrom each time window; create aggregated impedance signals using theimpedance signals from the different time windows; and analyze theaggregated impedance signals to detect PNS.
 2. The implantable medicaldevice according to claim 1, wherein said PNS detection module isconfigured to analyze the aggregated impedance signals to detectmorphological events and/or deviations indicating PNS by comparing saidgathered impedance signals with at least one impedance signal templateper time window.
 3. The implantable medical device according to claim 1,wherein said control module is configured to instruct said pacing moduleto deliver said pacing pulses at said different delays relative to theonset of the refractory period of the left ventricle in differentcardiac cycles, wherein the onset of the refractory period of the leftventricle is determined to be a delivery of a stimulation pulseresulting in a left ventricle contraction or a spontaneous ventriclecontraction.
 4. The implantable medical device according to claim 1,wherein said control module is configured to instruct said pacing moduleto deliver said pacing pulses via at least a first electrodeconfiguration and wherein said impedance measurement module isconfigured to measure at least one impedance signal using at least asecond electrode configuration.
 5. The implantable medical deviceaccording to claim 1, wherein said control module is configured to, atpredetermined time intervals or at receipt of an instruction, perform atemplate creation procedure.
 6. The implantable medical device accordingto claim 1, wherein said control module is configured to monitor changesin lead system criteria and, at detection of a change in at least onelead system criteria exceeding a predetermined threshold, to perform atemplate creation procedure and/or instruct said pacing module to changeelectrode configuration for delivery of pacing pulses and/or to issue analert.
 7. The implantable medical device according to claim 1, furthercomprising a posture sensor configured to sense a posture of the patientand/or an activity sensor configured to sense an activity level of thepatient.
 8. The implantable medical device according to claim 1, whereinsaid control module is configured to perform a template creationprocedure comprising: instructing said impedance measurement module tomeasure impedance signals in time windows in said refractory period ofthe left ventricle at predetermined delays relative to the onset of saidrefractory period of the left ventricle using at least one electrodeconfiguration; and instructing said PNS detection module to create twoor more impedance signal template using said gathered impedance signals.9. The implantable medical device according to claim 1, comprising aposture sensor configured to sense a posture of the patient and whereinsaid control module is configured to perform a template creationprocedure comprising: instructing said pacing module to deliver at leastone pacing pulse having a predetermined pulse amplitude and/or width inat least one time window within a refractory period of the leftventricle during a number of cardiac cycles for at least one posture,wherein pacing pulses are repeatedly delivered during a number ofcardiac cycles; instructing said impedance measurement module to measureimpedance signals in time windows synchronized with said delivery ofpacing pulses in said refractory period of the left ventricle using atleast one electrode configuration; and instructing said PNS detectionmodule to: gather impedance signals measured within said time windows ofsaid cardiac cycles for said different postures; and create two or moreimpedance signal templates for said at least one posture using saidgathered impedance signals.
 10. The implantable medical device accordingto claim 1, further comprising an activity sensor configured to sense anactivity level of the patient and wherein said control module isconfigured to perform a template creation procedure comprising:instructing said pacing module to deliver at least one pacing pulsehaving a predetermined pulse amplitude and/or width in at least one timewindow within a refractory period of the left ventricle during a numberof cardiac cycles at different activity levels, wherein pacing pulsesare repeatedly delivered during a number of cardiac cycles; instructingsaid impedance measurement module to measure impedance signals in timewindows synchronized with said delivery of pacing pulses in saidrefractory period of the left ventricle using at least one electrodeconfiguration; and instructing said PNS detection module to: gatherimpedance signals measured within said time windows of said cardiaccycles for said different activity levels; and create two or moreimpedance signal templates for each activity level using said gatheredimpedance signals.
 11. The implantable medical device according to claim1, wherein said control module is configured to perform a templatecreation procedure comprising: instructing said pacing module to deliverat least one pacing pulse having a predetermined pulse amplitude and/orwidth in at least one time window within a refractory period of the leftventricle during a number of cardiac cycles using different electrodeconfigurations, wherein pacing pulses are repeatedly delivered during anumber of cardiac cycles; instructing said impedance measurement moduleto measure impedance signals in time windows synchronized with saiddelivery of pacing pulses in said refractory period of the leftventricle using at least one electrode configuration; and instructingsaid PNS detection module to: gather impedance signals measured withinsaid time windows of said cardiac cycles; and create at least oneimpedance signal template for each electrode configuration using saidgathered impedance signals.
 12. The implantable medical device accordingclaim 8, wherein said PNS detection module is configured to: receive averification whether a PNS has occurred or not during the gathering ofimpedance signals, said verification being received from anextracorporeal unit via a communication module of said implantablemedical device; and determine whether a created impedance signaltemplate is a template with PNS content or without PNS content dependingon the received verification.
 13. The implantable medical deviceaccording to claim 8, wherein said PNS detection module is configuredto, during a template creation procedure, analyze the gathered impedancesignals to determine whether a PNS has occurred or not comprising: foreach time window, calculating the frequency content of the impedancewaveform; determining a frequency content related to respiration;detecting that a PNS has occurred if said frequency content related torespiration is above a predetermined frequency content threshold for aselected frequency range; and determine whether a created impedancesignal template is a template with PNS content or without PNS contentdepending on whether a PNS was detected or not.
 14. The implantablemedical device according to claim 1, wherein said control module isconfigured to, at regular intervals and/or at detection of a specificposture and/or a specific activity level and/or at occurrence of apredetermined hemodynamic event, perform a PNS test comprising:instructing said pacing module to deliver a pacing pulse having apredetermined pulse amplitude and/or width within a refractory period ofthe left ventricle, wherein pacing pulses are repeatedly deliveredduring a number of cardiac cycles; instructing said impedancemeasurement module to measure impedance signals in time windowssynchronized with said delivery of pacing pulses in said refractoryperiod of the left ventricle using at least one electrode configuration;and instructing said PNS detection module to: gather at least onemeasured impedance signal from each time window; and analyze thegathered impedance signals to detect morphological events and/ordeviations indicating PNS by comparing said gathered impedance signalswith an impedance signal template.
 15. The implantable medical deviceaccording to claim 1, wherein said control module is configured to:instruct said PNS detection module to: gather at least one measuredimpedance signal from each time window; and analyze the gatheredimpedance signals to identify a first pulse amplitude and/or width abovethe pacing therapy threshold that do not cause PNS; and wherein saidcontrol module is configured to determine an adequate PNS threshold gapto be the difference between the identified pulse amplitude and/or widthand the pacing therapy threshold.
 16. The implantable medical deviceaccording to claim 1, wherein said control module is configured toinitiate a PNS threshold test comprising: instructing said pacing moduleto deliver a pacing pulse within a refractory period of the leftventricle of said heart, wherein pacing pulses are repeatedly deliveredduring a number of cardiac cycles and wherein said pacing pulses havinga successively changed pulse amplitude and/or width; instructing saidimpedance measurement module to measure impedance signals in timewindows synchronized with said delivery of pacing pulses in saidrefractory period of the left ventricle using at least one electrodeconfiguration; and instructing said PNS detection module to: gather atleast one measured impedance signal from each time window; and analyzethe gathered impedance signals to detect morphological events and/ordeviations indicating PNS by comparing said gathered impedance signalswith impedance signal templates to identify pulse amplitudes and/orwidths that do not cause PNS; wherein said control module is configuredto determine the maximum pulse amplitudes and/or widths that do notcause PNS to be a PNS threshold.
 17. The implantable medical deviceaccording to claim 15, wherein said control module is configured todetermine a PNS threshold gap between a PNS threshold and a pacingtherapy threshold, wherein said control module is configured to, at aPNS threshold gap being below a predetermined value, perform anadaptation of pacing settings.
 18. The implantable medical deviceaccording to claim 15, wherein said control module is configured to, atdetection of PNS at a pulse amplitude and/or width below a predeterminedthreshold for a specific electrode configuration instruct said pacingmodule to change electrode configuration for delivery of pacing pulsesand/or adapt pulse amplitude and/or width.
 19. The implantable medicaldevice according to claim 6, wherein said control module is configuredto search for another electrode configuration comprising: selecting anelectrode configuration according to a predetermined order of a set ofconfigurations for delivery of pacing pulses; instructing said pacingmodule to deliver a pacing pulse having a predetermined pulse amplitudeand/or width within a refractory period of the left ventricle during anumber of cardiac cycles, wherein pacing pulses are repeatedly deliveredduring a number of cardiac cycles, for each of said electrodeconfigurations; instructing said impedance measurement module to measureimpedance signals in time windows synchronized with said delivery ofpacing pulses in said refractory period of the left ventricle using atleast one electrode configuration; and instructing said PNS detectionmodule to: gather impedance signals measured within said time windows ofsaid cardiac cycles; and analyze the gathered impedance signals todetect morphological events or deviations indicating PNS by comparingsaid gathered impedance signals with impedance signal templates; whereinsaid control module is configured to select the electrode configurationfor pacing stimulation that provides a predetermined PNS threshold gap.20. The implantable medical device according claim 1, wherein said PNSdetection module is configured to: for each time window, subtract eachimpedance sample from a corresponding impedance sample of a selectedimpedance signal template to obtain absolute difference values; processsaid absolute difference values to create an aggregated value for saidtime windows; compare said aggregated value with a predetermined limitbased on said template; and detect that a PNS has occurred if saidaggregated value is below said predetermined limit.
 21. The implantablemedical device according to claim 1, wherein said PNS detection moduleis configured to: for each time window, subtract each impedance samplefrom a corresponding impedance sample of a selected impedance signaltemplate to obtain absolute difference values; process said absolutedifference values to create an aggregated value for said time windows;compare said aggregated value with a predetermined limit based on saidtemplate; and detect that a PNS has occurred if said aggregated value isabove said predetermined limit.
 22. The implantable medical deviceaccording to claim 1, wherein said PNS detection module is configuredto: for each time window, cross-correlate an impedance signal during atime window with an impedance signal template for the corresponding timewindow to produce a first cross-correlation result; for each timewindow, cross-correlate an impedance signal template with itself toproduce a second cross-correlation result; calculate a difference valuefor each time window between the first and second cross-correlationresults; calculate a sum of all absolute difference values; compare saidsum with a predetermined limit value; and detect that a PNS has occurredif said aggregated value exceeds said predetermined limit value.
 23. Theimplantable medical device according to claim 1, wherein said PNSdetection module is configured to: for each time window, cross-correlatean impedance signal during a time window with an impedance signaltemplate for the corresponding time window to produce a firstcross-correlation result; for each time window, cross-correlate animpedance signal template with itself to produce a secondcross-correlation result; calculate a difference value for each timewindow between the first and second cross-correlation results; calculatea sum of all absolute difference values; compare said sum with apredetermined limit value; and detect that a PNS has occurred if saidaggregated value is below said predetermined limit value.
 24. Theimplantable medical device according to claim 1, wherein said PNSdetection module is configured to: for each time window, determine anumber of points in the impedance waveform where a derivative of theimpedance waveform shows a change of sign, wherein a new sign of thederivative lasts a predetermined period of time; and detect that a PNShas occurred if a difference between a determined number of points and areference number of points is higher than or equal to a predeterminedlimit value.
 25. The implantable medical device according to claim 1,wherein said PNS detection module is configured to: for each timewindow, calculate the frequency content of the impedance waveform;compare the calculated frequency content with a frequency content of aselected impedance template; and detect that a PNS has occurred if adeviation between the calculated frequency content and the frequencycontent of the selected impedance template is above a predeterminedfrequency content threshold for a selected frequency range.
 26. Theimplantable medical device according to claim 1, wherein said controlmodule is configured to, at regular intervals and/or at detection of aspecific posture and/or a specific activity level and/or at occurrenceof a predetermined hemodynamic event, initiate a PNS test comprising:instructing said pacing module to repeatedly deliver pacing pulseswithin a refractory period of the left ventricle of said heart during anumber of cardiac cycles, said pacing pulses having a predeterminedpulse amplitude and/or width; and instructing said impedance measurementmodule to measure impedance signals in time windows synchronized withsaid delivery of a pacing pulse in said refractory period of the leftventricle using more than one electrode configuration in a time windowor alternately using different electrode configurations for differenttime windows; instructing said PNS detection module to: gather at leastone measured impedance signal from each time window and for eachelectrode configuration; and analyze the gathered impedance signals todetect morphological events and/or deviations indicating PNS bycomparing said gathered impedance signals for each electrodeconfiguration with a corresponding impedance signal template for eachelectrode configuration and applying an PNS factor for each electrodeconfiguration.
 27. The implantable medical device according to claim 26,wherein said PNS detection module is, so as to detect morphologicalevents and/or deviations indicating PNS, configured to: calculate adifference waveform between a measured impedance waveform and eachcorresponding template for each electrode configuration; determine adifference value for each electrode configuration; multiply eachdifference value with the corresponding PNS factor to determine aresulting value for each electrode configuration; add the resultingvalues for all electrode configurations; and detect that PNS hasoccurred if the added resulting value is higher than a predetermined PNSthreshold.
 28. The implantable medical device according to claim 26,wherein said PNS detection module is configured to calculate a PNSfactor for each electrode configuration as reflecting a differencebetween an impedance signal template with PNS content and an impedancesignal template without PNS content for that specific electrodeconfiguration.
 29. The implantable medical device according to claim 26,wherein said control module is configured to instruct said pacing moduleto deliver pacing pulses having predetermined energies within arefractory period of the left ventricle, wherein pacing pulses arerepeatedly delivered during a number of cardiac cycles; wherein saidimpedance measurement module is configured to measure impedance signalsin time windows synchronized with said delivery of pacing pulses in saidrefractory period of the left ventricle using more than one electrodeconfiguration simultaneously or alternately using different electrodeconfigurations for different time windows; and wherein said PNSdetection module is configured to: gather at least one impedance signalfrom each time window and for each electrode configuration; andcalculate a PNS factor for each electrode configuration reflecting adifference between a frequency content in an impedance waveform with PNScontent and a frequency content in an impedance waveform without PNScontent.